System and method for evaluating tissue

ABSTRACT

The present invention provides a sensor system for measuring an elastic modulus and a shear modulus and a method for using the sensor system to evaluate a tissue by determining the presence of and/or characterizing abnormal growths. The method involves applying a set of forces of different magnitudes to one or more locations of tissue, detecting the corresponding displacements due to said applied forces, determining the forces acting on those locations of tissue which are a combination of forces from the applied voltages and the countering forces from tissue deformation, obtaining the elastic modulus and/or shear modulus for a plurality of locations, and determining abnormal growth invasiveness, malignancy or the presence of a tumor from said elastic and/or shear moduli.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. patent application Ser. No.12/992,923, filed on Mar. 8, 2011, currently pending, which is a 371 ofInternational application PCT/US2009/044250 filed May 15, 2009; and is anon-provisional of U.S. Provisional Patent Application No. 61/054,100,filed on May 16, 2008, pursuant 35 U.S.C. 119(e), the entire disclosureof which is incorporated herein by reference.

STATEMENT OF GOVERNMENT INTEREST

This invention was reduced to practice with Government support underGrant No. RO1 EB000720 awarded by the National Institutes of Health; theGovernment is therefore entitled to certain rights to this invention.

BACKGROUND OF THE INVENTION

1. Field of Invention

The present invention relates to a system and method for quantitativelyevaluating a tumor. More particularly, the invention involves using apiezoelectric sensor to detect the existence of, determine thedimensions of, determine the location of, identify the type of,determine the invasiveness of and/or determine the malignancy of atumor.

2. Brief Description of the Prior Art

The key to successful treatment of cancer lies in early detection; inturn, the early detection and identification of cancerous growths isheavily dependent upon the capability of sensors and screeningtechnologies. Currently, there are a variety of different sensors andtools used for investigating the mechanical properties of soft tissueand for imaging soft tissue.

One type of conventional soft tissue sensor uses an external forceapplicator for inducing displacement and an external displacement gaugefor measuring resistive force.^(1,2) The external force applicator maybe hydraulic or piezoelectric, and the external displacement gauge maybe optical or piezoelectric. These sensors, however, require theextraction and destruction of tissue specimens; during operation, sincethe specimens must be cut to conform with and fit within the sensor.

Exemplary soft tissue imaging tools include Computer Tomography (CT),Magnetic Resonance Imaging (MRI), Ultrasound (US), T-scan (TS) andUltrasound elastography (UE).³⁻⁸ CT scans¹⁰ take 360 degree X-raypictures and reconstructs 3D tissue structures using computer software.MRI scans¹¹ use powerful magnetic fields and radio waves to createtissue images for diagnosis. US scans¹² transmit high-frequency wavesthrough tissue and capture the echoes to image tissue structures. TS⁷measures low-level bioelectric currents to produce real-time images ofelectrical impedance properties of tissues. UE scans¹⁴ evaluate the echotime through tissue under a constant mechanical stress and compares itto that of the same tissue when unstressed. A tissue strain map is thenobtained, from which an image of 2D elastic modulus distribution iscreated by conventional inversion techniques.

Tactile imaging¹² tools, such as mammography, use array pressure sensorsto probe spatial tissue stiffness variations. Currently, mammography isused in breast cancer screening to detect abnormal tissue by tissuedensity contrast. Mammography is the only FDA approved breast cancerscreening technique, which has a typical sensitivity of 85% thatdecreases to 65% in radiodense breasts.⁹ However, in these screeningprocesses there is a high incidence of false positives. In fact, onlyabout 15-30% of breast biopsies yield a diagnosis of malignancy.Although effective for screening women over 40, mammography is not aseffective for screening women who have dense breast tissue.Additionally, mammography and other tactile imaging tools do not havethe ability to probe tumor interface properties.

Since many tissues harboring abnormal growths are stiffer than thesurrounding normal tissues under compression, detecting a change intissue stiffness has increasingly become an important factor indetection and diagnosis of abnormal tissue. For example, breast cancersare calcified tissues that are known to be more than seven times stifferthan normal breast tissue.¹⁰⁻¹³ Similarly, plaque-lined blood vesselsare also stiffer than normal, healthy blood vessels.

U.S. Pat. No. 7,497,133 discloses a piezoelectric finger sensor that maybe used to detect tumors by measuring tissue stiffness. Tumor mobilitywas assessed from the ratio of the shear modulus to the elastic modulus(G/E) ratio of the tumor or by sensitive direct tumor mobilitymeasurement using two piezoelectric finger sensors, one for pushing andone for measuring the movement of the tumor that results from thepushing. The patent concludes that the G/E ratio is higher in a tumorregion than the G/E ratio for surrounding normal tissue and that a muchhigher G/E ratio in the cancer region indicated that the tumor was lessmobile under shear than under compression, as compared to thesurrounding normal tissue. Although the patent concludes that thesemeasurements may offer the potential for non-invasive breast cancermalignancy screening, it does not disclose a method for determiningmalignancy, invasiveness or tumor type.

Consequently, there remains an important need to accurately andnon-invasively detect and identify tumors. Moreover, there exists a needto develop a means for probing tumor stiffness to determine the type,malignancy and/or invasiveness of the tumor.

SUMMARY OF THE INVENTION

In a first aspect, the invention relates to a sensor system formeasuring an elastic modulus and a shear modulus comprising a sensor, anapparatus for applying a voltage to a second electrode, a measuringmeans connected to said sensor; and a positioning means which may beautomated or manual for positioning said sensor.

In another aspect, the invention pertains to a method for evaluating atissue. The method involves applying a set of forces of differentmagnitudes to one or more locations of tissue, detecting thecorresponding displacements due to said applied forces, determining theforces acting on those locations of tissue which are a combination offorces from the applied voltages and the countering forces from tissuedeformation, obtaining the elastic modulus and/or shear modulus for aplurality of locations, and determining abnormal growth invasiveness,malignancy or the presence of a tumor from said elastic and/or shearmoduli.

In another aspect, the present invention provides the ability to measurethe dimensions and/or position of abnormal tissue in a tissue sample.The dimensions and/or position of abnormal tissue may be determined bymeasuring the elastic modulus and thickness of the tissue sample using aPEFS array having a plurality of PEFS' of different widths, i.e. tissuecontact regions. By measuring the elastic modulus of the tissue sampleusing PEFS' of different widths, and consequently different depthsensitivities, the elastic modulus and thickness of the abnormal tissueand the elastic modulus of the surrounding tissue can be calculated.From these calculations, the dimensions of the abnormal tissue as wellas the depth and position of the of the abnormal tissue within thetissue sample can be determined.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a schematic of a PEFS system including at least one PEFS, ameasuring means and an automated sensor positioning means.

FIG. 1B is a photograph of a PEFS.

FIG. 2A is a schematic of a PZT/stainless steel cantilever with drivingelectrode and a sensing electrode on a top side of the piezoelectriclayer.

FIG. 2B is a schematic of a PZT/stainless steel cantilever with adriving PZT layer and a sensing PZT layer and an L-shaped cantilever.

FIG. 2C is a schematic of a PZT/stainless steel cantilever with adriving PZT layer and a sensing PZT layer and a U-shaped cantilever.

FIG. 2D is a schematic of a PZT/stainless steel cantilever with adriving PZT layer and a sensing PZT layer and a square-shapedcantilever.

FIG. 3 is a schematic of a PEFS array.

FIG. 4A is a schematic of a PEFS being used for standard compressionmeasurement to determine elastic modulus.

FIG. 4B is a schematic of a PEFS being used for indentation compressionmeasurement to determine elastic modulus.

FIG. 4C is a schematic of a PEFS being used for standard shearmeasurement to determine shear modulus.

FIG. 4D is a schematic of a PEFS being used for indentation shearmeasurement.

FIG. 5A is a photograph of a smooth inclusion with the piezoelectriccantilever positioned for elastic modulus measurement.

FIG. 5B is a photograph of a rough inclusion with the piezoelectriccantilever positioned for shear measurement perpendicular to thedirection of the corrugation.

FIG. 6A is a graph of elastic modulus as a function of distance from thecenter of the inclusion in an x direction for smooth (full squares) andrough (open circles) inclusions made of C145.

FIG. 6B is a graph of elastic modulus as a function of distance from thecenter of the inclusion in a y direction for smooth (full squares) andrough (open circles) inclusions made of C145.

FIG. 7A is a schematic of a PEFS being used to apply a shear forceparallel to the direction of corrugation (x direction).

FIG. 7B is a schematic of a PEFS being used to apply a shear forceperpendicular to the corrugation (y direction).

FIG. 8A is a graph of shear modulus as a function of distance from thecenter of an inclusion in an x direction for smooth (full squares) andrough (open circles) inclusions made of C145.

FIG. 8B is a graph of shear modulus as a function of distance from thecenter of an inclusion in a y direction for smooth (full squares) andrough (open circles) inclusions made of C145.

FIG. 9A is a graph of G/E ratio as a function of distance in an xdirection for rough and smooth inclusions made of C54, C92, and C145.

FIG. 9B is a graph of G/E ratio as a function of distance in a ydirection for rough and smooth inclusions made of C54, C92, and C145.

FIG. 10A is a graph of elastic modulus as a function of inclusion depthfor rough and smooth inclusions made of C92.

FIG. 10B is a graph of shear modulus as a function of inclusion depthfor rough and smooth inclusions made of C92.

FIG. 10C is a graph of G/E ratio as a function of inclusion depth forrough and smooth inclusions made of C92.

FIG. 11 is a schematic of the scanning paths.

FIG. 12 is a graph of G/E ratio as a function of distance from thecenter of the inclusion at θ=0°, 30°, 60° and 90°.

FIG. 13A is a graph of elastic modulus as a function of depth formodeling clay inclusions embedded at various depths, shown in the insertfigure.

FIG. 13B is a graph of depth sensitivity limit as a function of thewidth of the PEFS contact area.

FIG. 14A is a schematic of two PEFS performing synchronized Young'smodulus measurement above the center of an inclusion embedded ingelatin.

FIG. 14B is a graph of elastic modulus as a function of inclusion depth.

FIG. 15A is a schematic of a PEFS performing elastic modulusmeasurements above the center of an inclusion of depth embedded in amatrix of gelatin.

FIG. 15B is a graph of elastic modulus as a function of inclusion depth

FIG. 16A is a graph of elastic modulus (E) and shear modulus (G)profiles as a function of distance for breast tissue.

FIG. 16B is a graph of shear modulus to Young's modulus ratio (G/E)profile as a function of distance for breast tissue.

FIG. 17A is a photograph of an excised breast tissue containing aninvasive ductal carcinoma.

FIG. 17B is an elastic modulus (E) scan of the excised breast tissueshown in FIG. 17A. The elastic modulus appears higher at the tumor sitethan at the surrounding tissue.

FIG. 17C is a shear modulus (G) scan of the excised breast tissue shownin FIG. 17( a). The shear modulus appears higher at the tumor site thanat the surrounding tissue.

FIG. 17D is a G/E scan of the excised breast tissue shown in FIG. 17(A).The G/E value>0.7 indicates that the boundary is rough, typical ofinvasive ductal carcinoma.

FIG. 18A is a photograph of an excised breast tissue containing a ductalcarcinoma in situ.

FIG. 18B is an elastic modulus (E) scan of the excised breast tissueshown in FIG. 18A. The elastic modulus appears higher at the tumor sitethan at the surrounding tissue.

FIG. 18C is a shear modulus (G) scan of the excised breast tissue shownin FIG. 18A). The shear modulus appears higher at the tumor site than atthe surrounding tissue.

FIG. 18D is a G/E scan of the excised breast tissue shown in FIG. 18A).The tumor G/E value of about 0.3 is consistent with noninvasive ductalcarcinoma confined within the milk duct.

FIG. 19A is a photograph of an excised breast tissue containing ahyperplasia.

FIG. 19B is an elastic modulus (E) scan of the excised breast tissueshown in FIG. 19A. The elastic modulus appears higher at the tumor sitethan at the surrounding tissue.

FIG. 19C is a shear modulus (G) scan of the excised breast tissue shownin FIG. 19A). The shear modulus appears higher at the tumor site than atthe surrounding tissue.

FIG. 19D is a G/E scan of the excised breast tissue shown in FIG. 19A),showing that the G/E value is about 0.5.

FIG. 20 is a graph of elastic and shear modulus of normal breast tissueas a function of patient age.

FIG. 21A is the E map of a mastectomy tissue sample.

FIG. 21B is the G map of a mastectomy tissue sample.

FIG. 21C is the G/E map of a mastectomy tissue sample.

FIG. 22 is a graph of tumor size measurements obtained by using the PEFSversus tumor size measurements obtained by pathology.

FIG. 23A is a photograph of a 4×1 compressive PEF array prototype with arobotic arm performing measurements on the right breast of a patient onher back.

FIG. 23B is a photograph of the PEFS array of FIG. 23A).

FIG. 24 is a graph of elastic modulus as a function of position on atissue.

FIG. 25 is a graph of depth sensitivity versus width/contact area of thePEFS or PEFS array.

FIG. 26A shows an array of 4 PEFS ready to be assembled.

FIG. 26B shows the PEFS array of FIG. 26A) clamped in position in theholder.

FIG. 26C shows the top of the holder of FIG. 26B).

FIG. 26D shows the bottom of the holder of FIG. 26B).

FIG. 27A is a diagram illustrating the elastic modulus E_(A) for atissue sample measured with a first PEFS having a first depthsensitivity D_(A).

FIG. 27B is a diagram illustrating the elastic modulus E_(B) for atissue sample measured with a first PEFS having a first depthsensitivity D_(B).

FIG. 27C is a diagram illustrating the elastic modulus E_(C) for atissue sample measured with a first PEFS having a first depthsensitivity D_(C).

FIG. 28 is a diagram illustrating the examination of a tissue modelhaving a top skin layer and a lower fat layer with a PEFS.

FIG. 29A is a diagram illustrating a tissue sample probed with 2 PEFS todetermine the depth of abnormal tissue in a breast tissue sample.

FIG. 29B is a diagram illustrating a tissue sample that needs to beprobed with 3 PEFS (E₁, E₂, and E₃) to determine the depth of abnormaltissue attached to the base of the breast.

FIG. 29C is a diagram illustrating a tissue sample that needs to beprobed with 4 PEFS (E₁, E₂, E₃, and E₄) to determine the depth ofabnormal tissue suspended within the breast.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT(S)

For illustrative purposes, the principles of the present invention aredescribed by referencing various exemplary embodiments thereof. Althoughcertain embodiments of the invention are specifically described herein,one of ordinary skill in the art will readily recognize that the sameprinciples are equally applicable to, and can be employed in otherapparatuses and methods. Before explaining the disclosed embodiments ofthe present invention in detail, it is to be understood that theinvention is not limited in its application to the details of anyparticular embodiment shown. The terminology used herein is for thepurpose of description and not of limitation. Further, although certainmethods are described with reference to certain steps that are presentedherein in certain order, in many instances, these steps may be performedin any order as may be appreciated by one skilled in the art, and themethods are not limited to the particular arrangement of steps disclosedherein.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural references unless thecontext clearly dictates otherwise. Thus, for example, reference to “asensor” includes a plurality of sensors and equivalents thereof known tothose skilled in the art, and so forth. As well, the terms “a” (or“an”), “one or more” and “at least one” can be used interchangeablyherein. It is also to be noted that the terms “comprising”, “including”,and “having” can be used interchangeably.

The present invention is directed to a system and method for evaluatingtissue, specifically soft tissue, to detect and/or identify an abnormalgrowth using a piezoelectric finger sensor (PEFS) system 100. The PEFSsystem may include at least one PEFS 1, a measuring means 2 and anautomated sensor positioning means 3. In an exemplary embodiment, PEFS 1may include both an actuator and sensor capable of being simultaneouslyoperated using a simple all electrical means.

In accordance with the method of the present invention, PEFS 1 may beused in vivo to measure elastic and shear properties of tissue. Byquantitatively determining the shear modulus, elastic modulus and/or theratio of shear modulus to elastic modulus (hereinafter referred to asthe “G/E ratio”) of the tissue, PEFS 1 may be used to determine theexistence, dimension, location, type, invasiveness and/or malignancy ofa tumor contained within the tissue. The method of the present inventionmay be used to detect, screen for, diagnose and/or confirm the presenceof various different forms of cancerous tissue and may be particularlysuitable for detecting breast cancer, prostate cancer, skin cancer orliver cancer.

1. Piezoelectric Finger Sensor (PEFS) System

As shown in FIG. 1, the PEFS system 100 of the present invention mayinclude at least one PEFS 1 attached to a measuring means 2 forgenerating an image, graphical or numerical representation of thespatial distribution of the elastic modulus, shear modulus and/or theG/E ratio of tissue. In an exemplary embodiment, the PEFS system mayfurther include an automated or manual sensor positioning means 3 thatis attached to and capable of positioning PEFS 1 relative to a tissuesurface.

The at least one PEFS 1 of the present invention may be constructed as acantilever, including at least one piezoelectric layer 4 bonded to atleast one non-piezoelectric layer 5 and including at least oneconductive element 6, 7 for applying a voltage to and relaying aninduced voltage from at least one piezoelectric layer 4. FIG. 2A showsone embodiment in which a driving electrode 6 and a sensing electrode 7are attached to the same side of piezoelectric layer 4. A thirdelectrode 6′ may be positioned on an opposite side of piezoelectriclayer 4. FIGS. 2B-2D show another embodiment including a firstpiezoelectric layer 4 with electrodes 6, 6′ on opposing surfaces fordriving PEFS 1, a non-piezoelectric layer and a second piezoelectriclayer 5′ with electrodes 7, 7′ on opposing surfaces for sensing adisplacement of PEFS 1. To facilitate simultaneous force application anddisplacement measurement, the present piezoelectric cantilever sensormay be constructed as a two circuit system. A first circuit may be usedto apply a driving force to PEFS 1. In an exemplary embodiment, theforce application circuit may contain a power supply 10 connected toelectrodes 6 and 6′ in a first embodiment shown in FIG. 2A.Alternatively, the power supply 10 may be connected to electrodes 6 and6′ across the first piezoelectric layer 4 in a second embodiment shownin FIGS. 2B-2D. A second circuit may be used to sense and quantitativelymeasure the displacement of the PEFS 1 that results from the applieddriving force. In an exemplary embodiment, the voltage measurementcircuit may contain a voltage measuring device 11 connected to electrode7 and 6′, as shown in the first embodiment shown in FIG. 2A.Alternatively, voltage measuring device 11 may be connected toelectrodes 7 and 7′ across the second piezoelectric layer 5′ in thesecond embodiment shown in FIGS. 2B-2D.

PEFS 1 may operate without sensing electrode 7 in the embodiment shownin FIG. 2A or without the second piezoelectric layer 5′ and electrodes 7and 7′ in the embodiment shown in FIGS. 2B-2D. These components may bereplaced with other means for measuring displacement of thepiezoelectric cantilever under compression or shear, such as a laser ora piezoelectric displacement meter. However, without the self-sensingcapability provided by electrode 7 in the first embodiment or the secondpiezoelectric layer 5′ and electrodes 7 and 7′ in the second embodiment,the device would not be capable of in vivo or in situ measurements oftissues having complex shapes.

PEFS 1 may have a variety of different shapes and configurations thatfacilitate tissue analysis. Exemplary configurations may include anL-shaped, U-L-shaped, U-shaped, square-shaped, rectangle-shaped,O-shaped or tapered structure having various lengths and widths. In anexemplary embodiment, PEFS 1 may have an L-shaped tip adapted toaccurately measure the shear modulus of soft tissues and materials undera negligible degree of strain of less than about 0.1% so as to avoid anypatient discomfort. Preferably, PEFS 1 is constructed as a smallcantilever probe having one or more cantilevered fingers suitable fordetecting prostate cancer, breast cancer, skin cancer or liver cancer.

In an exemplary embodiment, PEFS 1 is a cantilever all-electrical sensorcapable of simultaneously applying a force to tissue and detecting thecorresponding induced displacement of the tissue. This ability toself-excite and self-detect enables PEFS 1 to directly measure theelastic and shear moduli of specimens having complex shapes using itscantilevered tip. In operation, the tip of the PEFS 1 cantilever ispositioned adjacent to and/or in contact with a tissue surface. Avoltage is then applied to driving electrode 6 of piezoelectric layer 4in order to generate a bending force that induces a correspondingdisplacement of PEFS 1. When the sensor tip is in contact with thetissue, the displacement of cantilever will be altered by the resistanceof the tissue, with stiffer tissue producing less bending. The net forceacting on the tissue is therefore the combination of the force generatedby the applied voltage and the countering force resisting tissuedeformation. Bending of the PEFS 1 cantilever generates an inducedpiezoelectric voltage in the bottom sensing PZT layer in proportion tothe displacement at the cantilever tip. The displacement of thecantilever tip may be measured by detecting the induced piezoelectricvoltage from sensing electrode 7. Carefully monitoring the displacementat the cantilever tip during a given test provides an accuratemeasurement of the force exerted on and the resulting displacement of atissue surface. This information may then be used to accuratelydetermine the mechanical properties of the tissue sample. For example,the slope of the net force versus displacement plot, may be used todetermine the elastic modulus, shear modulus or G/E ratio of the tissue.PEFS 1 may have a high degree of detection sensitivity. In an exemplaryembodiment, PEFS 1 may have a depth detection sensitivity that is abouttwice the width of PEFS 1. For example, a 1 cm wide PEFS 1 may becapable of measuring, detecting and analyzing tissue up to a depth ofabout 2 cm.

In an exemplary embodiment, PEFS system 100 may include several PEFS 1arranged in an array to facilitate real-time compression and shearmeasurement. PEFS arrays of varying probe widths or identical probewidths ranging from less than 1 millimeter to several centimeters may beconstructed to assess stiffness variations of soft materials/tissues upto tens of centimeters in depth with increased spatial resolution ofless than one-millimeter. The depth sensitivity may be further enhancedand customized by adjusting the width of the PEFS contact area. Thepreferred PEFS width may range from 1-15 mm to provide adequatemeasurement speeds. The PEFS array may have any configuration anddimension; preferably, the array may have a contact surface of about 5to 10 cm in diameter. The array may be formed from PEFS of anydimension. In an exemplary embodiment, the PEFS array may be fabricatedfrom PEFS with a contact area of about 0.1×0.1 mm to about 10×10 mm. ThePEFS may have a dimension of about 1-10 mm wide by about 1-3 cm long. Asshown in the exemplary embodiment of FIG. 3, each PEFS may be providedwith a long driving PZT layer on one side of a stainless steel sham anda shorter sensing PZT layer on the other side of the stainless steelsham. The PEFS's of the array may all be oriented perpendicular to atissue surface, as depicted in FIGS. 4C-4D, for measuring the shearmodulus. Alternatively, the PEFS's of the array may be oriented parallelwith a tissue surface, as depicted in FIGS. 4A-4B, for measuring theelastic modulus.

The PEFS array may include a plurality of PEFS of uniform or varyingdimensions, forming a tissue contact surface of suitable dimensions. ThePEFS array may be fabricated by cutting previously bonded PZT/stainlesssteel bi-layer or PZT/stainless steel/PZT multi-layer into parallel PEFSusing a diamond-saw or wire-saw cutter. These individual PEFS 1 may thenbe arranged and assembled in an array, as shown in FIG. 3. In anexemplary embodiment, the array may be customized to correspond to thecontours and dimensions of a particular tissue surface.

Moreover, in addition to facilitating the detection process, the PEFSarray increases depth sensitivity. The depth detection sensitivity of anarray of PEFS 1 may be about twice the combined width of the PEFS 1 ofthe array. Arranging several PEFS in an array and synchronizing themeasurements of neighboring PEFS 1 induces multiple PEFS' 1 to behave asa single sensor having a wide contact surface, thereby increasing thedepth sensitivity of the device.

PEFS system 100 may further include a measuring means 2 operativelyassociated with PEFS 1 or an array of PEFS's 1. Measuring means 2 may beany electrical device, such as an oscilloscope or a voltage metercoupled with a computer, capable of measuring a displacement of thecantilever in the form of an induced voltage between electrodes 7 and 6′across the piezoelectric layer 4 in the first embodiment shown in FIG.2A or an induced voltage between electrodes 7 and 7′ of the secondpiezoelectric layer 5′ in the second embodiment shown in FIG. 2B, thatmay be used together with the applied force to obtain aforce-displacement plot whose slope may be used to deduce elasticmodulus, shear modulus and/or a G/E ratio for the tested tissue.Measuring means 2 may be capable of numerically, graphically orotherwise displaying the measurements obtained from PEFS 1 and/orcalculations based on these measurements, including the elastic modulus,shear modulus and/or G/E ratio. In one embodiment, measuring means 2 maybe capable of analyzing the data and expressing the location of tissueabnormalities in polar coordinates so as to graphically and accuratelylocate the abnormal tissue within or relative to the tested tissue. Inan exemplary embodiment, the measuring means 2 may be a portableelectrical measurement unit capable of handling multiple measurementsfrom a plurality of PEFS's 1 in an array. Preferably, the measuring unitmay also be programmed to automatically deduce the elastic modulus,shear modulus and/or G/E ratio associated with a particular tissuesample.

In an exemplary embodiment, the measuring means 2 enables real timeimaging and/or graphical representation of these calculations.Preferably, the measuring means 2 may employ data processing speedswhich enable real time in vivo data processing, scanning and imaging.More preferably, the measuring means 2 may be portable and may enablevisualization of the analyzed data and/or calculated properties of thetissue. In an exemplary embodiment, measuring means 2 may be a portableunit the size of a pocket calculator and may run on electricity or abattery-based power source.

PEFS 1 or an array of PEFS 1 may also be attached to an automated and/ormanual positioning means 3 that facilitates the positioning of the PEFS1 relative to the soft tissue. Although the PEFS 1 may be manuallyplaced on a tissue surface, the automated positioning means 3, as shownin FIG. 1, may be employed to more efficiently, more quickly and/or moreaccurately position PEFS 1. Furthermore, the automated positioning means3 may be used to move PEFS 1 from location to location, speeding up themeasuring process and facilitating in vivo clinical application of thedevice. In an exemplary embodiment, the automated positioning means 3may be a programmable robotic arm capable of 3-D automated positioning,such as the CrustCrawler AX-12 Smart Arm w/CM-5 Bundle. Alternatively,automated positioning means 3 may also be a three-dimensional positionerusing a set of stepping motors.

2. Method for Using the Piezoelectric Finger Sensor (PEFS) System

The method of the present invention is a noninvasive method of using aPEFS 1 to determine the type, invasiveness and/or malignancy of a tumorcontained within a tissue. The method involves placing a PEFS 1 or anarray of PEFS 1 in contact with a tissue surface. In an exemplaryembodiment, PEFS 1 may be applied to a tissue surface in a mannersimilar to manual palpation by contacting and rubbing the tissuesurface. PEFS 1 therefore functions like an electronic finger thatenables electronic palpation by electrically applying a force to andelectronically measuring a displacement of the tissue.

PEFS 1, as shown in FIG. 2B, may be operated by applying a voltage topiezoelectric layer 4 of PEFS 1. The voltage causes PEFS 1 to bend dueto the converse piezoelectric effect, which generates a force anddisplacement at the sensor's cantilever tip. The bending of thecantilever generates an induced piezoelectric voltage in a piezoelectriclayer 4 or 5 of PEFS 1 in proportion to the displacement at thecantilever tip. Therefore, by carefully monitoring the displacement ofthe cantilever tip and determining the net force exerted on the tissuewhich is a combination of the force from the applied voltage and thecountering force from tissue deformation, it is possible to determinethe elastic modulus and shear modulus of a particular tissue samplebased on the displacement of the cantilever tip, relative to theexpected displacement of the tip in the absence of the tissue sample.The displacement measurements may be used to determine the elasticmodulus, shear modulus and G/E ratio for a particular tissue sample.

To measure the elastic modulus, PEFS 1 may be placed in contact with atissue surface, as shown in FIG. 5A. When a voltage is applied to PEFS1, a force is exerted by the PEFS on the tissue in a directionorthogonal to the tissue surface, inducing vertical displacement of thetip of PEFS 1 into the plane of the tissue. By measuring the appliedforce and the resultant displacement of the cantilever tip, it ispossible to determine net force exerted on the sample and obtain theelastic modulus of the tissue from the slope of the force-displacementcurve. The PEFS 1 may be used to directly determine the elastic modulusof tissue in any direction, including the length, width or thickness ofa tissue sample. The measured elastic modulus may, in some cases, beemployed to screen for the presence of abnormal tissue. Specifically,tissue having an abnormally large elastic modulus may indicate thepresence of abnormal tissue.

To measure the shear modulus, PEFS 1 may be placed in contact with atissue surface, as shown in FIG. 5B. A voltage is applied to PEFS 1inducing exertion of a force on the tissue in a direction parallel tothe tissue surface and consequently, producing a horizontal displacementof the PEFS 1 tip. By measuring the applied force and the resultantdisplacement of the cantilever tip, it is possible to determine the netforce exerted on a tissue and deduce the shear modulus of the tissuefrom the net force-displacement curve. PEFS 1 may be used to directlydetermine the shear modulus of tissue with the shear movement in anydirection, including the length or the width direction of a tissuesample. The measured shear modulus distribution map may be used as ascreening test to determine for the presence of abnormal tissue.Specifically, tissue having an abnormally large shear modulus mayindicate the presence of abnormal tissue.

A shear modulus measurement indicative of a smooth interfacial area maybe an indicator of a non-invasive tumor whereas a shear modulusmeasurement representative of a rough and branchy interfacial area maybe an indicator of an invasive tumor. Without wishing to be bound bytheory, it is thought that the shear modulus measurement is differentfor invasive and non-invasive tumors when measured in a particulardirection which is preferably perpendicular to the interfacial branchyand rough protrusions of invasive tumors because the interlocking natureof the tissue in the interfacial area of invasive tumors renders thetissue specimen less mobile in the interfacial area than the tissue inthe interfacial area for less interconnected non-invasive tumors.Similarly, the shear modulus may also provide a means for determiningmalignancy.

While either an elastic modulus distribution map or a shear modulusdistribution map of a tissue sample may assist in determining thelocation, dimension and depth of a tumor, as well as the presence ofabnormal tissue, a comparison of the G/E ratio of tissue samples enablesfurther information to be determined about the abnormality. In anexemplary embodiment, the elastic and/or shear modulus distribution mapmay extend to an area of normal/healthy tissue in order to providebaseline elastic and/or shear modulus values for normal/healthy tissue.In this manner, the procedure can be carried out on any patient since noassumptions need to be made regarding the elastic or shear modulus ofnormal/healthy tissue for that patient because the present methodactually measures these values. Also, the accuracy and specificity ofthe present predictive method is enhanced since measured values fornormal/healthy tissue of each patient are used as a basis for comparisonthereby allowing for variations in the stiffness of tissue in differentpatients.

The G/E ratio is the ratio of the shear modulus to the elastic modulusfor a particular tissue sample. Specifically, such a comparison may beused to determine information about the properties of the interfacialarea of abnormal tissue, which may be used to assess tumor malignancy,invasiveness and, in some cases the type of tumor.

If it is known from the individual shear and/or elastic modulusdistribution map that abnormal tissue is present, a low G/E ratio lessthan about 0.7, more preferably, about 0.5 or less and most preferably,about 0.3 or less at the location of abnormal tissue may be indicativeof a non-invasive tumor such as carcinoma in situ and a high G/E ratioof 0.7 or larger may be indicative of an invasive tumor such as invasivecarcinoma. Similarly, G/E ratio may also be used to determinemalignancy. The first step to determining malignancy is identifyingwhether the tumor is confined by a tissue boundary which would otherwisealter the stiffness characteristics of the tissue. If the tumor is notconfined, a G/E ratio of 0.7 or greater may be indicative of malignancy.If the tumor is confined, such as is the case for malignant ductalcarcinoma in situ, a G/E ratio of about 0.3 or larger may be indicativeof malignancy.

Notably, PEFS system 100 and the method of the present invention areextremely effective and accurate, achieving about 100% sensitivity indetecting breast abnormalities; about 96% sensitivity and about 54%specificity in detecting malignancy or invasive carcinoma with G/E>0.7for a tumor that is not confined or a G/E>0.3 for a tumor that isconfined and about 89% sensitivity and about 82% specificity indetecting malignancy with a G/E>0.7. For mechanically dense breasttissue the method achieved is about a 94% sensitivity and about 63%specificity for detecting malignancy with a G/E>0.7 for a tumor that isnot confined or a G/E>0.3 for a tumor that is confined; and about 93%sensitivity and about 80% specificity for detecting malignancy inmechanically dense breast tissue with a G/E>0.7.

For purposes of the present application, specificity for malignancy isthe number of non-cancer predictions divided by the number of actualnon-cancer pathological diagnosis multiplied by 100. Specificity forinvasive carcinoma is the number of non-invasive carcinoma predictionsdivided by the number of actual non-invasive carcinoma pathologicaldiagnosis multiplied by 100. For purposes of the present application,sensitivity for malignancy is the number of cancer predictions dividedby the number of actual cancer pathological diagnosis multiplied by 100.Sensitivity for invasive carcinoma is the number of invasive carcinomapredictions divided by the number of actual invasive carcinomapathological diagnosis multiplied by 100. Accuracy for malignancy is thesum of the number of cancer predictions confirmed by cancer pathologicaldiagnosis and the number of non-cancer predictions confirmed bynon-cancer pathological diagnosis divided by the total number of casesmultiplied by 100. Accuracy for invasive carcinoma is the sum of thenumber of invasive carcinoma predictions confirmed by invasive cancerpathological diagnosis and the number of non-invasive cancer predictionsconfirmed by non-invasive cancer pathological diagnosis divided by thetotal number of cases multiplied by 100.

One advantage of the invention is that it provides significantly lessfalse positive readings than current mammography techniques, therebyminimizing the need to perform numerous unnecessary tissue biopsies forthe false positive results of the mammograms.

Another potential advantage of the present invention is that it has avery high sensitivity indicating that there is a very low likelihoodthat cancerous tissue would be overlooked using the method of thepresent invention. This is important because it ensures that the methodof the present invention, used alone, may be a reliable cancer screeningmethod.

The G/E ratio may also be used to identify specific types of malignantor benign tumors. Specifically, a G/E ratio of about 0.5, morepreferably about 0.5 to 0.6, may be indicative of hyperplasia, and a G/Eratio of about 0.3, more preferably about 0.2-0.4 combined with anidentification of the presence of abnormal tissue obtained from one ormore of the individual shear and elastic modulus maps of the sample, maybe indicative of carcinoma in situ or benign tumors, such as fibrocysticor fibroadipose. Although healthy tissue may also exhibit G/E ratiosabout 0.3, cancerous tissue and tumors having a G/E ratio in this rangecan still be identified by its higher shear and elastic modulus thanthat of the healthy surrounding tissue. It has been found, for example,that a benign tumor may have a G/E ratio of about 0.3, the same as forhealthy tissue, but that the individual measurements of shear modulusand elastic modulus of the benign tumor are typically higher than theindividual measurements of shear modulus and elastic modulus for healthytissue, thereby allowing the prediction of the presence of a benigntumor under these circumstances.

In the case of carcinoma in situ, it may be necessary to also considerthe location of the tissue in question to complete the prediction ofwhether there is cancerous tissue or not. In this case, the surroundingtissue of, for example, a milk duct, can confine the cancerous tissue,thereby altering the shear and/or elastic moduli of the cancerous tissuein the interfacial area. As a result, the carcinoma in situ willtypically exhibit a G/E ratio of about 0.3 due to confinement of theinterfacial area by the surrounding tissue. However, individual shearand elastic modulus measurements can again be used to predict thepresence of the carcinoma in situ under these circumstances since theindividual shear and elastic moduli will differ from that of healthytissue. Although benign tumors such as fibrocystic tumors also exhibit ahigher shear modulus and elastic modulus value than those of thesurrounding healthy tissue, inclusion of abnormal tissue as identifiedby the individual elastic modulus map or shear modulus map that exhibita G/E about 0.3 would still allow positive predictions of all carcinomasin situ.

The method of the present invention may further involve the step ofartificially increasing the perceived interfacial roughness of a tumorin order to enhance the sensitivity of the indicator for malignancy,invasiveness or tumor type. The perceived interfacial roughness may alsobe enhanced for examination of tumors located at a significant depthbelow the tissue surface or tumors which have developed largeinterlocking networks. In an exemplary embodiment, the perceivedinterfacial roughness may be increased by increasing the angle of thescan path relative to the interfacial protrusions. For purposes of thepresent invention, the angle of the scan path refers to the orientationof PEFS 1 relative to the interfacial protrusions when the shear forceis applied. Different scan angles are achieved by rotating PEFS 1, shownin FIG. 5B, about its longitudinal axis, relative to the tissue sample.Preferably, the angle is at least 30 degrees, more preferably, at least60 degrees and, most preferably, about 90 degrees.

Upon analyzing and diagnosing the tissue sample, measuring means 2 maybe used to express the location of tissue abnormalities in polarcoordinates so as to graphically and accurately locate the abnormaltissue within or relative to the tested tissue based on the elasticmodulus, shear modulus and/or G/E measurements. Additionally, measuringmeans 2 may be also be used to quantitatively determine and map the sizeand depth of the tissue abnormalities. In an exemplary embodiment, thelocation and dimensions of the abnormal tissue may be displayed on a 2Dor 3D map to facilitate surgery.

The PEFS system 100 and method of the present invention are particularlyadvantageous in comparison to the tumor detection and evaluation methodsof the prior art. The method of the present invention is capable ofscreening for the type, invasiveness and malignancy of a tumor byquantitatively measuring tissue stiffness and is not dependent upon thedensity difference between the tumor and the surrounding tissue orangiogenesis. These quantitative measurements may be unilaterally anduniformly used by any oncologist or physician to render an objectivedetermination as to the presence of, dimension of, location of, type of,invasiveness of and/or malignancy of a tumor without requiring theinterpretation of a highly trained radiologist.

Furthermore, the method and system 100 of the present invention is ahighly effective means for evaluating tissue specimens and isparticularly well suited for in vivo tissue imaging. The PEFS system 100is sensitive and capable of detecting minute tumors less than about 0.5cm (in a demonstrated case, the cancer was 3 mm in size) that arefrequently missed by mammography, ultrasound, and/or palpation, whichtypically have a size sensitivity limitation of about 1 cm. The PEFS isextremely accurate and highly sensitive, producing results unmatched bycurrently existing technologies. In comparison to screening tests suchas mammography, magnetic resonance imaging, ultrasound imaging andSureTouch™ imaging, the PEFS system 100 has a higher sensitivity andspecificity for identifying the presence of a tumor as well as forpredicting malignancy and tumor invasiveness. The depth sensitivity maybe further enhanced or customized by changing the width of the PEFSsensor or PEFS array, as discussed above.

Another particularly advantageous feature of the present invention isthe ability to detect tumors, malignancies and invasive carcinomas inmechanically dense tissue. For example, in breast cancer detection, thedevice of the present invention is suitable for both heterogeneouslydense tissue which is defined as being composed of 51-75% glandulartissue and extremely dense tissue which is defined as being greater than75% glandular tissue. These definitions are taken from the BI-RADSBreast Imaging Lexicon found athttp://www.radiologyassistant.nl/en/4349108442109 which classifiesmammographic breast tissue composition into four distinct categories.This is important since human females under 40 years of age tend to havebreast tissue that falls into one of these two categories andmammographic imaging methods are not well-suited for distinguishingtumors from, for example, extremely dense breast tissue.

Moreover, because the PEFS system 100 of the present invention does notoperate on radiation or electromagnetic waves, patients are not exposedto potentially harmful effects as a result of the testing and may repeatthe testing at any time without concern for adverse health risks. Thismay be particularly beneficial for physicians attempting to track fastgrowing cancers. By contrast, screening procedures such as mammography,may only be preformed once a year. The method of the present inventionis also noninvasive and gentle, requiring a strain of less than 1%,thereby causing minimal to no patient discomfort. Furthermore, the PEFSsystem 100 is also portable, inexpensive and may be mass produced withrelative ease, making it capable of being widely implemented.

In another aspect, the present invention provides the ability to measurethe dimensions and/or position of abnormal tissue in a tissue sample.The dimensions and/or position of abnormal tissue may be determined bymeasuring the elastic modulus and thickness of the tissue sample andabnormal tissue using a PEFS array having a plurality of PEFS' 1 ofdifferent widths, i.e. tissue contact regions. In an exemplaryembodiment, a PEFS' array having 3 or more PEFS' 1 may be used toanalyze abnormal tissue positioned on or near the surface of the tissue,and a PEFS′ array having 5 or more PEFS' 1 may be used to detectabnormal tissue suspended in or supported on a distal bottom surface ofthe tissue. By measuring the elastic modulus of the tissue sample usingPEFS' 1 of different widths, and consequently different depthsensitivities, the elastic modulus and thickness of the abnormal tissueand the elastic modulus of the surrounding tissue can be calculated.From these calculations, the dimensions of the abnormal tissue as wellas the depth and position of the of the abnormal tissue within thetissue sample can be determined. The length and width of the abnormaltissue can be determined from the tissue map as described above.

The depth and position of the abnormal tissue can be determined using aPEFS array with 3 PEFS' 1 having a depth sensitivity of h₁, h₂, and h₃,the elastic elastic moduli for each of these PEFS', E₁, E₂, and E₃, maybe obtained in the manner discussed above. By solving the equations(1)-(3) below,

$\quad\begin{matrix}\begin{matrix}{{{For}\mspace{14mu} {Cantilever}\mspace{14mu} 1\text{:}\mspace{14mu} \frac{1}{E_{1}/h_{1}}} = {\frac{1}{{Es}/{ts}} + \frac{1}{{Ef}/\left( {h_{1} - {ts}} \right)}}} & {\mspace{85mu} (1)} \\{{{For}\mspace{14mu} {Cantilever}\mspace{14mu} 2\text{:}\mspace{14mu} \frac{1}{E_{2}/h_{2}}} = {\frac{1}{{Es}/{ts}} + \frac{1}{{Ef}/\left( {h_{2} - {ts}} \right)}}} & (2) \\{{{For}\mspace{14mu} {Cantilever}\mspace{14mu} 3\text{:}\mspace{14mu} \frac{1}{E_{3}/h_{3}}} = {\frac{1}{{Es}/{ts}} + \frac{1}{{Ef}/\left( {h_{3} - {ts}} \right)}}} & (3)\end{matrix} & \;\end{matrix}$

it is then possible to determine the elastic modulus and thickness (i.e.depth) of the abnormal tissue, E_(s) and t_(s), respectively, as well asthe elastic modulus, E_(f), of the surrounding tissue. This methodologyis exemplified in Example 11 below.

Previously we have described a two-spring model that measures the depthof a bottom-supported tumor embedded inside tissues (See Rev. Sci.Instr. 78, 115101 (2007)). The present invention extends this to coverthe situation where the effect of a bottom-supported tumor isdetermined, as well as to make depth determinations in the situationwhere the tumor is suspended above the bottom support.

Bottom-Supported Inclusions

Three piezoelectric fingers (PEFs) are used for this determination, asshown in FIG. 29B. FIG. 29A illustrates the situation where the bottomsupport is not considered. This situation is discussed above.

For bottom-supported inclusions it is desirable to determine the elasticmodulus of the normal tissue, E_(g), the elastic modulus of the abnormaltissue, E_(i), the elastic modulus of the bottom support (i.e. chestwall for breast tissue), E_(b), the depth or height from the surface tothe bottom support, h_(t), and the depth or height to the top of theabnormal tissue, h_(i).

Using a first PEF with depth sensitivity h₁<h_(t), the followingequations can be developed:

Away from the inclusion: E₁=E_(g)

Above the inclusion: h ₁ /E ₁ =h _(i) /E _(g)+(h ₁ −h _(i))/E _(i,)

Using a second PEF with depth sensitivity h₂<h_(t), the followingadditional equation can be developed:

Above the inclusion: h ₂ /E ₂ =h _(i) /E _(g)+(h ₂ −h _(i))/E _(i).

Using a third PEF with depth sensitivity h₃>h_(t), the followingadditional equations can be developed:

Away from the inclusion: h ₃ /E ₃ =h _(t) /E _(g)+(h ₃ −h _(t))/E _(b),

Above the inclusion: h ₃ /E ₃ =h _(i) /E _(g)+(h _(t) −h _(i))/E _(i)+(h₃ −h _(t))/E _(b).

With the five equations we can solve for the five unknowns: E_(g),E_(i), E_(b), h_(i), and h_(t). It can be verified that the PEFscorrespond to PEF1, PEF2, and PEF3. When PEF1 and PEF2 are used, awayfrom the inclusion the E values are the same and are smaller than whenPEF3 is used. Also, above the inclusion, E₃ should be larger than E₁ andE₂.

Suspended Inclusions

This is the situation of FIG. 29C and for this situation a fourth PEF isrequired. For suspended inclusions it is desirable to determine theelastic modulus of the normal tissue, E_(g), the elastic modulus of theabnormal tissue, E_(i), the elastic modulus of the bottom support (i.e.chest wall for breast tissue), E_(b), the depth or height from thesurface to the bottom support, h_(t), the depth or height from thesurface to the bottom of the abnormal tissue, h_(ib), and the depth orheight to the top of the abnormal tissue, h_(i).

Using a first PEF with depth sensitivity h₁<h_(t), we have the followingequations:

Away from the inclusion: E₁=E_(g)

Above the inclusion: h _(t) /E ₁ =h _(i) /E _(g)+(h ₁ −h _(i))/E _(i)

Using a second PEF with depth sensitivity h₂<h_(t), we have thefollowing equation:

Above the inclusion: h ₂ /E ₂ =h _(i) /E _(g)+(h ₂ −h _(i))/E _(i)

Using a third PEF with depth sensitivity h₃>h_(t), we have the followingequations:

Away from the inclusion: h ₃ /E ₃ =h _(t) /E _(g)+(h ₃ −h _(t))/E _(b),

Above the inclusion: h ₃ /E ₃ =h _(i) /E _(g)+(h _(ib) −h _(i))/E_(i)+(h _(t) −h _(ib))/E _(g)+(h ₃ −h _(t))/E _(b).

Using the fourth PEF with h_(t)>h₄>h_(ib), we have following equation:

Above the inclusion: h ₄ /E ₄ =h _(i) /E _(g)+(h _(ib) −h _(i))/E_(i)+(h ₄ −h _(ib))/E _(g).

With these six equations we can solve for the five unknowns: E_(g),E_(i), E_(b), h_(i), h_(ib), and h_(t). The identify of PEF4 can beverified since away from the inclusion for PEF4, E₄=E₁=E₂. Above theinclusion, E₄ may be smaller or larger than E₂, but must be smaller thanE₃. Meanwhile, away from the inclusion, E₃>E₁=E₂=E₄ and above theinclusion E₃>E₄.

It is envisioned that the PEFS system 100 will assist physicians inscreening for tumors and various forms of cancer, including but notlimited to breast cancer, prostate cancer, skin cancer or liver cancer,prior to or in conjunction with procedures such as biopsy, surgicalprocedures, mammography, magnetic resonance imaging, ultrasound imaging,or other radioactive or electromagnetic screening tests. The PEFS system100 of the present invention may either be used independently or inconjunction with traditional screening methods to assist in the earlydetection of tumors or diagnosis/confirmation of cancer. It is furtherenvisioned that because this novel method and PEFS system 100 may beused to detect millimeter-sized tumors that are typically missed bytraditional screening methods, it may be particularly beneficial forearly cancer detection. Also, since the present method does not rely ontissue density, it may also be particularly useful in women for whomtraditional screening methods are ineffective due to tissue densityissues. It may also be used for cancer/tumor monitoring for treatmentevaluation. It may also be used before surgery to locate thecancer/tumor to help guide surgeons.

Additionally, the PEFS system 100 may also be used in the field ofdermatology for testing skin elasticity, cellular elasticity/plasticityor other tissue related properties. Of course, the PEFS system 100 maybe effectively used in conventional methods for making compression andshear measurements on pliable materials of any kind. It is to beunderstood that the PEFS system 100 is not intended to be limited toapplications involving tissue measurements.

EXAMPLES Example 1

A study was performed to determine the effectiveness of the PEFS of thepresent invention to accurately evaluate a set of artificial tissues,which mimic the physical properties of various types of tumors. The PEFSwas used to determine whether the artificial tumors embedded in theartificial tissue samples have a rough or branchy interfacial surface, apotential indicator of invasive malignant cancer such as malignantbreast cancer, by measuring the elastic modulus (E), shear modulus (G)and determining the G/E ratio for the artificial tissues. It was foundthat either the elastic modulus or the shear modulus may be used todiscern the dimensions of the artificial tumor, and that the shearmodulus may further be used to characterize the texture of interface ofa tumor with the surrounding tissue. Additionally, when the shearmodulus was measured using a scan path substantially perpendicular tothe direction of corrugation at the interface of the tissue, a G/E ratioof greater than about 0.7 was found when probing malignant tissue.

The piezoelectric cantilever used in the study, which is schematicallyshown in FIG. 4A), was constructed to have a 22±0.2 mm in length toplayer of lead zirconate titanate (PZT) (T105-H4E-602, Piezo SystemsInc., Cambridge, Mass.) and a 11±0.2 mm long bottom layer of PZT bondedto a 50-μm thick stainless steel layer (Alfa Aesar, Ward Hill, Mass.)located between the PZT layers using a nonconductive epoxy (HenkelLoctite Corporation, Industry, Calif.) cured at room temperature for oneday. The cantilever was 3.8±0.2 mm wide. Both the top and bottom PZTlayers were 127 μm thick. The top PZT layer was used for forceapplication. When a voltage was applied across the thickness of the topPZT layer, it created a lateral strain in the top PZT layer due to theconverse piezoelectric effect of the top PZT layer. The created strainbends the cantilever. The force produced by the cantilever bending wascalibrated for force application.¹⁴ The bottom PZT layer was used as adisplacement meter. Upon bending of the cantilever, a voltage differencewas generated across the thickness of the bottom PZT layer due to thedirect piezoelectric effect and the axial displacement of the cantileverwas calibrated with the induced voltage across the bottom PZT layer.¹⁵Thus, with both the top and bottom PZT layers, the cantilever was ableto both apply a force and provide a displacement sensor in one deviceusing simple electrical means. ¹⁵ The stainless steel tip was furtherfashioned into a square loop at the free end with each side of thesquare equal to the width of the cantilever to facilitate bothcompression and shear measurements using the same cantilever. Thecantilever was clamped with a fixture made of 7.5 mm thick acrylic(McMaster-Carr, New Brunswick, N.J.). The PZT layers had a piezoelectriccoefficient, d₃₁=−320 pC/N as specified by the vendor. The elasticmodulus of the stainless steel and that of the PZT layers were 200 GPaand 62 GPa, respectively according to the vendors. The capacitance andthe loss factor of a PZT layer were measured using an Agilent 4294AImpedance Analyzer (Agilent, Palo Alto, Calif.). The contact area of thesquare stainless steel loop was 3.8 mm×3.8 mm. The effective springconstant, K, of the cantilever was 143 N/m as determined using apublished procedure.¹⁵ A DC power supply, HP E3631A, (Hewlett-PackardCompany, Palo Alto, Calif.) was used as the programmable DC voltagesource. The measurements were obtained using a Newport optical table(RS1000, Newport Corporation, Irvine, Calif.) to minimize low-frequencybackground vibrations. The applied voltages across the driving PZT layerand the induced voltage across the sensing PZT layer were recorded on anAgilent Infiniium S4832D digital oscilloscope (Agilent, Palo Alto,Calif.). The DC power source and the oscilloscope were connected to apersonal computer (PC). All voltage measurements, real-time elasticmodulus computations, and data acquisition were controlled from a PC byLabView (National Instrument, Austin, Tex.) programming.

The artificial tissues tested in the study were constructed by embeddingmodeling clay in gelatin (Fisher Scientific, Pittsburgh, Pa.). Threetypes of modeling clays were used: Modeling clay C54 (Play-Doh, HasbroLtd., Newport, UK) with an elastic modulus of 54±12 kPa. Modeling clayC92 (Model Magic, Crayola, Easton, Pa.) with an elastic modulus of 92±9kPa, and modeling clay C145 (Modeling Clay, Crayola, Easton, Pa.) withan elastic modulus of 145±10 kPa. In order to evaluate the interfacialproperties of different tumors, each type of modeling clay was molded toform two types of inclusions 8 of the same size, about 22 mm long, 12 mmwide, and 14 mm high, having different surface textures. A firstinclusion 8 fabricated with a smooth top surface S, as shown in FIG. 5A,represented benign tumors and a second inclusion 8 with a corrugated topsurface R, as shown in FIG. 5B, represented malignant tumors. Thecorrugated surface mimicked the physical properties of the branchy orroughened interfacial area of malignant tumors. All R inclusions hadrectangular grooves 2-4 mm wide and 7 mm deep running along the width ofthe inclusions. After formation, the modeling clay inclusions wereembedded in a matrix 9, such as gelatin, wherein the top of theinclusion surface was 3 mm from the top gelatin surface. Theconcentration of the gelatin matrix 9 was 0.21 g/ml prepared by mixing57.75 g of gelatin (Fisher Scientific, Pittsburgh, Pa.) in 275 ml ofwater at 80° C. on a hot plate for 5 min. After placing each of thesamples in a dish, the gelatin mixture was poured over the samples tothe desired height, cooled at 5° C. for 1 hr to facilitatesolidification and then equilibrated at room temperature for 1 hr priorto measuring.

The elastic modulus (E) of the artificial tissue samples was used todetermine the dimension of a tumor. The elastic modulus of the sampleswas measured using the PEFS in the indentation mode^(16,17) such thatthe cantilever was oriented parallel to the artificial tissue surface,as shown in the photograph in FIG. 5A. When a voltage V_(a), was appliedto the driving PZT layer of the cantilever, it generated a forceproducing a vertical displacement d (indentation) into the tissue,thereby inducing a voltage, V_(in), across the sensing PZT layer. Theelastic modulus, E, of the tissue is related to the applied force F,contact area, A, and vertical tissue displacement, d, as

$\begin{matrix}{{E = {\frac{1}{2}\left( \frac{\pi}{A} \right)^{\frac{1}{2}}\left( {1 - v^{2}} \right)\frac{F}{d}}},} & (1)\end{matrix}$

where v the Poisson's ratio of the tissue. Because the tip displacement,d, of the measuring cantilever is linearly proportional to V_(in), theelastic modulus, E, can be conveniently expressed in terms of V_(in) as

$\begin{matrix}{{E = {\frac{1}{2}\left( \frac{\pi}{A} \right)^{\frac{1}{2}}\left( {1 - v^{2}} \right)\frac{K\left( {V_{{in},0} - V_{in}} \right)}{V_{in}}}},} & (2)\end{matrix}$

where K is the spring constant of the measuring cantilever, V_(in,0) isthe induced voltage across the sensing PZT layer of the measuringcantilever without the tissue. Thus, by knowing the V_(in,0) before handand by measuring V_(in) at various V_(p), the elastic modulus, E, of thetissue can be deduced by plotting

${\frac{1}{2}\left( \frac{\pi}{A} \right)^{\frac{1}{2}}\left( {1 - v^{2}} \right){K\left( {V_{{in},0} - V_{in}} \right)}\mspace{14mu} {versus}\mspace{14mu} V_{in}},$

and conveniently done through LabView. The measurement detail can befound in Ref 18.

The elastic moduli of each inclusion obtained by scanning along the xand y directions are termed E_(x) and E_(y), respectively. Note that allthe S inclusions and R inclusions had the same length, width, andheight, only differing in the fact that the S inclusions had a smoothtop surface while the R inclusions had a corrugated surface. The scannedarea for each inclusion and its vicinity was 44 mm×68 mm with a 4 mminterval.

As an example, the elastic modulus profiles in the x direction and thosein the y direction of the C145 modeling clay S and R inclusions areshown in FIG. 6A and FIG. 6B, respectively. E_(x,S) and E_(x,R) are theelastic moduli of the S and R inclusions, in the x direction along thecenter line of the inclusions, respectively, as schematically shown inthe insert in FIG. 6A, and E_(y,S) and E_(y,R) are the elastic moduli ofthe S and R inclusions in they direction along the center line of theinclusions, as schematically shown in the insert in FIG. 6B. Clearly,E_(x,S), E_(x,R), E_(y,S), and E_(y,R) were all about 52±3 kPa above theinclusions and dropped to a constant value of about 9±1 kPa away fromthe inclusions, indicating that the elastic modulus measurement wasindependent of the surface roughness and scan direction. The elasticmodulus of the gelatin matrix away from the inclusions was about 9±1kPa. The length and width of the model tumors were estimated based onthe width at half the peak height, which indicates a length of about19±1 mm and about 20±1 mm and a width of about 9±1 mm and about 9.4±1 mmfor the S and R inclusions, respectively. These figures are in agreementwith the known lengths and widths of the S and R inclusions.

The shear modulus, when measured perpendicular to the direction ofcorrugation of the artificial tissue samples, was used to discern thetexture of the interfacial area of the artificial tumor, which may be anindicator of malignancy. The shear modulus of the tissue was measuredusing the indentation shear experimental method wherein the cantileverwas oriented perpendicular to the tissue surface, as shown in FIG. 5B.In this geometry, a force, F, parallel to the tissue surface was exertedon the tissue when a voltage, V_(a), was applied to the driving PZTlayer of the measuring cantilever, producing a horizontal displacement,d, to the tissue and an induced voltage, V_(in), to the sensing PZTlayer. The shear modulus G of the tissue can be empirically expressed interms of the horizontal force, F, the horizontal displacement, d, andthe contact area, A as:

$\begin{matrix}{{G = {\alpha \; \frac{1}{2}\left( \frac{\pi}{A} \right)^{\frac{1}{2}}\left( {1 - v^{2}} \right)\frac{F}{d}}},} & (3)\end{matrix}$

where α is a constant determined empirically. Experimentally, α wasfound to be 1±0.2. Because the induced voltage of the sensing PZT layeris proportional to the horizontal displacement of the tissue, similarly,the shear modulus, G, can be deduced using the induced voltage as

$\begin{matrix}{{E = {\frac{1}{2}\left( \frac{\pi}{A} \right)^{\frac{1}{2}}\left( {1 - v^{2}} \right)\frac{K\left( {V_{{in},0} - V_{in}} \right)}{V_{in}}}},} & (4)\end{matrix}$

which can be obtained by measuring V_(in) and plotting

$\frac{1}{2}\left( \frac{\pi}{A} \right)^{\frac{1}{2}}\left( {1 - v^{2}} \right){K\left( {V_{{in},0} - V_{in}} \right)}$

versus V_(in) using LabView.

For shear measurements, the PEFS was displaced parallel to thecorrugation (i.e., the displacement is in the x-direction) asschematically shown in FIG. 7A, and perpendicular to the corrugation(i.e., the displacement is in the y direction), as schematically shownin FIG. 7B. The shear modulus was measured both with the contact areamoving parallel to the corrugation, as shown in FIG. 7A, andperpendicular to the corrugation, as shown in FIG. 7B. Since thecorrugation resides in the x direction of FIGS. 7A and 7B, the measuredshear modulus in which the contact area was moved parallel to thecorrugation is G_(x) and the measured shear modulus in which the contactarea was moved perpendicular to the corrugation is G_(y). Similarly,G_(x) and G_(y) are also measured over the S inclusions.

The shear modulus profiles in the x direction and those in the ydirection are shown in FIGS. 8A and 8B, respectively, where G_(x,S) andG_(c,R) were respectively the shear moduli of the S and R inclusionsmeasured with the shear motion in the x direction (parallel to thecorrugation of the R inclusions) along the center line of the inclusionsas schematically shown in the insert in FIG. 8A. G_(y,S) and G_(y,R)are, respectively, the shear moduli of the S and R inclusions measuredwith the shear motion in they direction (perpendicular to thecorrugation of the R inclusions) along the center line of the inclusionsas schematically shown in the insert in FIG. 8B. For the S inclusion,both G_(x,S) and G_(y,S) were about 16±1 kPa above the inclusionindependent of the shear direction and fell off to about 3±1 kPa awayfrom the inclusion. In contrast, for the R inclusion, the shear modulusmeasured perpendicular to the corrugation, G_(y,R), and was found to be37±2 kPa above the inclusion whereas the shear modulus measured parallelto the corrugation, G_(x,R), was about 16±1 kPa. The length and width ofthe S and R inclusions as estimated from the width at half the peakheight were 19.2±1 mm and 19.8±1 mm, 9.8±1 mm and 9.6±1 mm,respectively, in agreement with those obtained from the elastic modulusprofiles and with the known values. Away from the inclusion both G_(y,R)and G_(x,R) fell off to a constant value of about 3±1 kPa. The aboveresults indicate that surface roughness played a role in the shearmodulus measurements above the inclusion. When the shear motion wasparallel to the direction of corrugation, the measured shear modulus ofa corrugated inclusion was similar to that of a smooth inclusion. On theother hand, when the shear motion was perpendicular to the direction ofcorrugation, the measured shear modulus was more than twice that of asmooth inclusion. Finally, the constant value of about 3±0.5 kPa inG_(y,S), G_(y,S), G_(x,S) and G_(x,R) away from the inclusionscorresponded to the shear modulus of the gelatin matrix.

The ratio of the shear modulus, when measured perpendicular to thedirection of corrugation, to the elastic modulus (G/E), was used todetermine malignancy. It is known that Poisson's ratio, v, of anisotropic tissue or soft material is 0.5, which gives a G/E ratio ofabout 0.3. We plot G_(x,S)/E_(x,S) and G_(x,R)/E_(x,R) in FIG. 9( a) forthe S and R inclusions and G_(y,S)/E_(y,S) and G_(y,R)/E_(y,R) in FIG.9B for the S and R inclusions. Note that FIGS. 9A and 9B include theresults from the S and R inclusions made from all three differentmodeling clays, C54, C92 and C145, which is also summarized in Table I.

TABLE I Sample Measurements Elastic Modulus Shear ModulusG_(y,S)/E_(y,S,) Elastic Modulus Shear Modulus Sample Interface(E_(y,S), E_(y,R)) G_(y,S), G_(y,R)) G_(y,R)/E_(y,R) (E_(x,S), E_(x,R))(G_(x,S), G_(x,R)) G₂/E₂ C54 Smooth 33.6 ± 1.9 kPa  9.9 ± 0.3 kPa 0.2930.5 ± 4.7 kPa  8.7 ± 0.1 kPa 0.29 C92 Smooth 43.4 ± 2.9 kPa 13.1 ± 0.6kPa 0.30 41.8 ± 3.2 kPa 12.7 ± 0.3 kPa 0.30 C145 Smooth 51.6 ± 2.7 kPa16.2 ± 0.7 kPa 0.31 49.2 ± 2.5 kPa 15.2 ± 1.0 kPa 0.31 C54 Rough 32.3 ±2.8 kPa 24.8 ± 1.0 kPa 0.77 29.3 ± 2.3 kPa  8.5 ± 0.3 kPa 0.29 C92 Rough41.4 ± 1.7 kPa 30.0 ± 1.1 kPa 0.72 41.4 ± 1.6 kPa 12.6 ± 0.9 kPa 0.30C145 Rough 51.7 ± 2.5 kPa 37.1 ± 1.6 kPa 0.72 50.5 ± 3.2 kPa 15.6 ± 1.1kPa 0.31

FIG. 9A shows that for all the S inclusions, the G/E ratio remainedaround 0.3 above or away from the inclusion in both the x and ydirection. FIG. 9B shows that unlike that of the S inclusions, the G/Eratio of all the R inclusions (G_(y,R)/E_(y,R)) was larger than 0.7above the inclusion when the shear measurement was perpendicular to thedirection of corrugation and fell off to about 0.3 away from theinclusion. In contrast, the G/E ratio of the R inclusions(G_(x,R)/E_(x,R)) was constant at about 0.3 above or away from theinclusion when the shear measurement was parallel to the direction ofcorrugation. As can be seen, the enhanced shear modulus of the Rinclusions, when measured perpendicular to the corrugation, translatedto an enhanced G/E ratio much larger than the 0.3 expected of isotropicsoft tissues.

The shear modulus, when measured perpendicular to the direction ofcorrugation, was more than twice that measured parallel to thecorrugation or that measured over a smooth inclusion. As a result, theG/E ratio was enhanced to over 0.7 above a rough inclusion when measuredperpendicular to the corrugation, in contrast to the G/E ratio of asmooth inclusion or that of a rough inclusion measured parallel to thecorrugation. Without wishing to be bound by theory, the enhanced shearmodulus, and hence the enhanced G/E ratio over a rough inclusion whenmeasured perpendicular to the direction of corrugation, was due to theinterlocking nature of the corrugated surface which rendered it harderfor either the gelatin or the modeling clay to move horizontally whensubject to a shear stress.

To investigate whether the G/E ratio would change with a differentdegree of interfacial roughness, the E and G were measured along a scanpath at an angle, θ to the x-axis, as schematically shown in FIG. 11.The obtained G/E ratio versus distance from the center of the inclusionat various θ is shown in FIG. 12. With respect to FIG. 12, all distanceswere normalized, such that the inclusions had the same width at allangles for easier comparison. As can be seen, the G/E ratioprogressively increased from 0.33 for θ=0 (parallel to corrugation) toabove 0.7 for θ=90° above the rough inclusion, whereas for the smoothinclusion, the G/E ratio remained around 0.33 regardless of the angle θand whether it was above the inclusion or the gelatin. While changingthe angle of the scan path relative to the direction of corrugation wasnot the only way to artificially increase the interfacial roughness, itserved to illustrate that G/E ratio of the inclusion increased with theartificial increase in interfacial roughness as θ increased from 0 to90° .

Additionally, the tested PEFS contact size was 3.8 mm, which was largerthan the groove width, 2 mm. Therefore, most likely, in mostmeasurements, the contact area either covered only a modeling-clay toothor part of a modeling-clay tooth and part of a groove. Under suchconditions, the depth of the R inclusion was essentially the depth ofthe modeling clay teeth, which was what was used for comparison in thisstudy. However, if the contact size were smaller than the groove size,the measured shear modulus might differ depending on whether themeasurement was above a tooth either partially or completely or entirelyabove a groove. The shear modulus measured above a tooth would besimilar to what we measured in this study whereas that measured above agroove may be different as the groove had a much larger depth than theteeth.

Example 2

A PEFS was investigated to determine the depth sensitivity of elasticmodulus measurements. The PEFS was fabricated from two piezoelectriclayers, namely, a top 127 um thick PZT layer (105-H4E-602, Piezo System,Cambridge, Mass.) that functioned to drive a bottom 127 um thick sensingPZT layer bonded to a 50 um thick stainless steel layer (Alfa Aesar,Ward Hill, Mass.). The stainless steel layer formed a square tip at adistal end of the PEFS that was used to perform compression and sheartests.

To determine the depth sensitivity of the PEFS, artificial tissuesamples were prepared by embedding modeling clay model inclusions,having an elastic modulus of about 80 kPa, in a gelatin matrix, whichhas an elastic modulus of about 4±1 kPa, at various depths ranging from2 to 17 mm, as shown in FIG. 13A). The elastic moduli of the modeltissues were then measured by indentation compression tests using threePEFS of various widths, namely 8.6 mm, 6.1 mm and 3.6 mm. The resultantelastic moduli of the model tissues were then plotted versus the depthat which the modeling clay were embedded in the gelatin matrix, as shownin FIG. 13A. The white, green and red bars correspond to elastic modulimeasured by the 8.6 mm, 6.1 mm, and 3.6 mm wide PEFS, respectively. Ascan be seen, the elastic moduli of the model tissues were essentiallythe same as that of gelatin matrix at a depth of ≧8 mm (red), ≧12 mm(green), and ≧16 mm (black), for the 3.6 mm (red), 6.1 mm (green), and 86 mm (black) wide PEFS, respectively. FIG. 13B shows a graph of theresultant depth sensitivity limit, which proves that the depthsensitivity limit of a PEFS is approximately twice the width of thecontact area.

Example 3

The depth sensitivity of the PEFS of Example 1, defined as the maximumdepth for which it is possible to obtain an accurate measurement, wasinvestigated to determine sensor accuracy and reliability. Specifically,the depth sensitivity of the PEFS was investigated for determining theshear modulus and the G/E ratio of a tissue sample. Similar to previousstudies which have confirmed that elastic modulus measurements areaccurate to a depth sensitivity of about twice the size of the contactarea of the PEFS, the depth limit for shear modulus measurements and theG/E ratio was also found to be about twice the size of the contact area.

The shear modulus of seven S inclusions embedded in artificial tissuesamples and seven R inclusions embedded in artificial tissue sampleswere investigated. Each inclusion was about 22 mm long and 12 mm wideand was made of C92 modeling clay, which has an elastic modulus thatclosely mimics that of breast tumors. The inclusions were embedded atvarying depths within a gelatin matrix. The depths of the inclusionswere as summarized in Table II.

TABLE II Inclusion Depth S Inclusion # R Inclusion # Depth (mm) 1 1 1.72 2 3 3 3 4.7 4 4 7 5 5 8.6 6 6 10.1 7 7 11.6The inclusions were embedded in a gelatin having an elastic modulus of3±0.2 kPa and shear modulus of 1±0.2 kPa as determined on a separategelatin sample prepared in the same manner. The elastic moduli and shearmoduli of the seven S inclusions and seven R inclusions were measuredabove the centers of the inclusions and the shear moduli of the Rinclusions were measured perpendicular to the direction of corrugation.

FIG. 10A shows the resultant elastic modulus versus inclusion depth forboth the S inclusions (open circles) and the R inclusions (opensquares). The shaded horizontal band, shown in FIG. 10A, represents theelastic modulus of the gelatin matrix with its experimental uncertainty.Empirically, the depth sensitivity of the elastic modulus measurement isthe depth at which the measured elastic modulus of an inclusion becameindistinguishable from that of the gelatin matrix. As can be seen, themeasured elastic modulus versus depth of the S inclusions correspondedto that of the R inclusions, both exhibiting a depth sensitivity ofbetween 7 mm and 8 mm, about twice the 3.8 mm width of the cantilever.

FIG. 10B shows the measured shear modulus versus depth for the Sinclusions (open circles) and the R inclusions (open squares). Theshaded horizontal band indicated the value of the shear modulus of thegelatin matrix with its standard deviation. As can be seen, the depthsensitivity for the shear modulus of the S inclusions and the Rinclusions were also found to be about 8 mm, similar to the depthsensitivity found when measuring the elastic modulus. In FIG. 10C, theG/E ratio versus the inclusion depth is plotted for both the Sinclusions (open circles) and the R inclusions (open squares). For the Sinclusions, the G/E ratio remained around 0.3 as expected for alldepths. For the R inclusions, the G/E remained around 0.7 for depthssmaller than 8 mm The value of the G/E ratio decreased when the depthbecame larger than 8 mm and became 0.3 when the depths were larger than10 mm. From FIG. 10C, the depth sensitivity of the present 3 8 mm widecantilever was around 8 mm, about twice the size of the contact area(which was width of the cantilever.

Example 4

The depth sensitivity of a PEFS array was also investigated. It wasfound that PEFS arrays have enhanced depth sensitivity in comparison toa single PEFS.

The study involved performing depth-sensitivity measurements using anarray of two 3.8 mm wide PEFS's. The PEFS's were arranged side by side,as schematically shown in FIG. 14A, to measure the elastic modulus of anartificial tissue containing modeling-clay inclusions 8 of variousdepths, similar to those shown in the insert in FIG. 13. The two PEFS'swere placed at the center above each model inclusion. The measurementsby the two PEFS's were synchronized. That is, the applied voltages tothe driving PZT layers of both PEFS's were applied at the same time withthe same magnitude. The induced voltages at the sensing PZT layers ofthe two PEFS's were also measured at the same time. As previouslydetermined in Example 2, the depth sensitivity of a PEFS is about twicethe width of the PEFS. By synchronizing the measurements of twoneighboring PEFS's, the PEFS array acted as one large PEFS. Thereforethe combined width of the PEFS's enhanced the overall depth sensitivity.FIG. 14B shows a graph of the measured elastic modulus as a function ofmeasured inclusion depth d obtained from the synchronized PEFS array.

For comparison, depth sensitivity measurements were also performed usinga single PEFS at the center location above the inclusion asschematically shown in FIG. 15A. FIG. 15B shows the elastic modulus as afunction of depth for both the PEFS and PEFS array. The synchronizedmeasurements enabled the PEFS array to detect inclusions up to 13 mm indepth, while the single PEFS could only detect inclusions less than 7 mmdeep. The results shown in FIGS. 14-15 indicated that the depthsensitivity of the PEFS array doubled, relative to a single PEFS. Thedepth sensitivity of synchronized PEFS arrays will be roughly twice thewidth of the contract area of the array.

Example 5

Sample excised breast tissues were evaluated to determine the type,malignancy, invasiveness and depth of the tumor within the tissuesamples.

In one portion of the study, the shear moduli of excised breast tissueswere measured by indentation shear tests using a 8 mm wide PEFS. FIG.16A shows the shear modulus profile for a sample excised breast tissuecontaining an invasive and malignant ductal carcinoma. FIG. 16A alsoshows the elastic modulus profile measured with the same PEFS. As can beseen, like the elastic modulus measurement, the indentation shearmeasurement is capable of detecting the higher shear modulus of thetumor as compared to the shear modulus of the surrounding tissue.

Moreover, the G/E ratio was usable to discern the roughness of theinterface between the inclusion 8 and the surrounding matrix 9. In FIG.16B, the shear modulus is plotted as a function of the G/E ratio anddemonstrates that the G/E ratio of the tumor was well over 0.7 ascompared to the G/E ratio of about 0.3 of the surrounding tissue. Thisresult evidences that high G/E ratios greater than about 0.3 may becorrelated to invasive cancers.

FIG. 17A shows an excised breast tissue containing an invasive ductalcarcinoma. FIGS. 17B, 17C and 17D show the elastic modulus scan, theshear modulus scan and the G/E scan, respectively, where the light colorrepresents low E, G, and G/E values of the surrounding tissues and thedark color represents high E, G, and G/E values. Clearly, both the E andG scans identified the location of the tumor depicted by the dark highelastic modulus and high shear modulus area of the tumor as compared tothe surrounding tissue. Furthermore, the G/E for the tumor was >0.7,indicating that the tumor had a rough boundary in comparison to thesurrounding tissue, consistent with the invasive nature of an invasiveductal carcinoma.

FIG. 18A shows a photograph of an excised breast tissue containing aductal carcinoma in situ (DCIS). FIGS. 18B, 18C and 18D show the elasticmodulus (E) scan, the shear modulus, G, scan, and the G/E scan,respectively. The E and G values were higher at the tumor site than forthe surrounding tissue, indicating an abnormality. The G/E ratio wasabout 0.3 at the tumor site, similar to the G/E ratio of the surroundingtissue, which is consistent with the fact that a ductal carcinoma insitu is confined within the milk duct and is not invasive.

FIG. 19A shows an excised breast tissue containing a hyperplasia. FIGS.19B, 19C and 19D show the elastic modulus (E) scan, the shear modulus,G, scan and the G/E scan, respectively. The E and G values were higherat the tumor site than for the surrounding tissue, indicating anabnormality. The G/E ratio was about 0.5, indicating that the boundaryof a hyperplasia is rougher than a ductal carcinoma in situ but not asrough as an invasive ductal carcinoma.

As noted by the evaluating surgeon, hyperplasia is difficult to identifyby palpation. Pathologically, it is an abnormal growth with no clearboundary. Therefore, because a PEFS can detect hyperplasia in both E andG scans and this example has shown that hyperplasia exhibits a differentG/E ratio from an invasive ductal carcinoma or a ductal carcinoma insitu, it can be used as a sensitive and robust screening tool fordetecting various types of breast abnormalities.

A total of 42 ex vivo breast tissue samples were evaluated and comparedto pathology tissue analysis. The types of tumors are listed in TableIII.

TABLE III Distribution of G/E among various breast abnormalities G/E =0.3 G/E = 0.5 G/E > 0.7 Sub Total Malignant Invasive Carcinoma 1 23 24Ductal Carcinoma in situ 7 1 8 Benign 10 Hyperplasia 7 1 8 Fibrocystic 11 Fibroadipose 1 1 Total 42

The PEFS measurements indicated that invasive carcinoma exhibited a G/Eratio>0.7 (23 out of 24), hyperplasia had a G/E ratio=0.5 (7 out 8),ductal carcinomas in situ had a G/E ratio of ˜0.3 (7 out 8) andfibrocystic and fibroadipose exhibited a G/E ratio=0.3 (2 out of 2).

As shown in Table IV, the malignancy of the tumors was also evaluated interms of the G/E ratio of the tissue samples.

TABLE IV Malignancy Analysis Malignant Benign G/E = 0.3 or >0.7 32(TP) 3(FP) 35 (TP + FP) G/E = 0.5  0(FN)  7(TN)  7(FN + TN) Total 32(TP +FN) 10(FP + TN) 42(TP + FP + TN + FN)

Using a G/E ratio>0.7 or equal to 0.3 as a criterion for malignancy, thesensitivity for malignancy was 100% (32 out of 32). The specificity was70% (7 out 10), and the accuracy was 93% (39 out 42). The positiveprediction value was 91% (32 out of 35), and the negative predictionvalue was 100% (7 out 7). These results are listed in Table V, below.

TABLE V Statistics of 42 excised breast tissues Sensitivity SpecificityAccuracy PPV* NPV** Malignancy 100% (32/32) 70% (7/10)  93% (39/42) 91%(32/35) 100% (7/7)   Invasiveness  96% (23/24) 89% (16/18) 93% (39/42)92% (23/25) 94% (16/17)

As can be seen, the PEFS achieved 100% sensitivity, 70% specificity, and93% accuracy for malignancy.

TABLE VI Invasiveness analysis Invasive Non-invasive G/E > 0.7 23(TP) 2(FP) 25(TP + FP) G/E < 0.7  1(FN) 16(TN) 17(FN + TH) Total 24(TP + FN)18(FP + TN) 42(TP + FP + TN + FN)

In addition, using a G/E ratio of >0.7 as a criterion, it was alsopossible to differentiate invasive tumors, such as invasive carcinoma,from non-invasive tumors, such as ductal carcinoma, as shown in Table VIabove. The sensitivity was 96% (23 out 24); the specificity was 89% (16out 18); and the accuracy was 93% (39 out 42). The positive predictionvalue was 92% (23 out 25), and the negative prediction value was 94% (16out 17). These results are also listed in Table V. As can be seen, PEFSachieved 96% sensitivity, 89% specificity, and 93% accuracy forpredicting invasive carcinoma.

Additionally, as part of the study, two PEFS's of different widths wereused to perform elastic modulus profile measurements on the same tumorto determine the tumor depth and tumor elasticity simultaneously withoutsimulations. FIG. 16A shows the elastic modulus profile of a tumor usingan 8 mm wide and 3 mm wide PEFS. From FIG. 16A, one can see that usingtwo PEFS's of different widths, the resultant elastic modulus profileswere different due to the different depth sensitivity limits of the twoPEFS's. From the two elastic modulus profiles, it was possible to deducethe elastic modulus, E_(t), and depth of the tumor, d, using thefollowing equations:

$\begin{matrix}{{\frac{d_{1}}{E_{1}} = {\frac{d}{E_{n}} + \frac{d_{1} - d}{E_{t}}}},{and}} & (5) \\{{\frac{d_{2}}{E_{1}} = {\frac{d}{E_{n}} + \frac{d_{2} - d}{E_{t}}}},} & (6)\end{matrix}$

d₁ and d₂ are the depth sensitivity limits and E₁ and E₂ are themeasured elastic modulus of PEFS 1 and PEFS 2, respectively, and E_(n)is the elastic modulus of the normal breast tissues. Using the measuredelastic modulus over the center of the tumor, using the depthsensitivity limits and E_(n) obtained from a flat tissue region locateda distance from the tumor, it was possible to determine that d=5 mm andE_(t)=68 kPa. The lateral size of the tumor was 6 mm, as estimated fromthe lateral elastic modulus and shear modulus profiles.

Example 6

The ex vivo breast tissue experiment of Example 5 above was subsequentlycontinued, the resulting data for which is provided below. In total 71breast tissue samples were evaluated and compared to pathology tissueanalysis.

FIG. 20 shows a graph of E and G of the normal breast tissues of the 71breast tissue samples as a function of patient age. As can be seen, boththe E and G varied with age with younger women exhibiting both a higherE and a higher G. The E of the normal breast tissue was about 18 kPa forwomen who were about 24 and about 18 to about 15 kPa for women who were24-40. Similarly, the G of the normal breast tissue was about 6 to about5 kPa for women were 24-40 and decreased to about 3 kPa for women about90 years old. The results demonstrate a strong correlation between thevalues of E and G of normal breast tissue and patient age, with youngerwomen exhibiting higher E and G.

The average E and G of the normal breast tissues of all 71 samples wasE_(n,ave)=13±3 kPa, and G_(n,ave)=4.4±1 kPa, where n denotes normaltissue. Of the 71 cases, there were 33 cases of invasive carcinoma (IC)(32 cases of invasive ductal carcinoma and 1 case of invasive lobularcarcinoma), 9 cases of ductal carcinoma in situ (DCIS), and 19 cases ofbenign conditions (BC) including fibrocystic, hyperplasia,calcifications, fibroadenoma, papilloma, and glandular tissues.

As an example, FIGS. 21A-21B show the E map of a mastectomy sample withan insert showing a PEF in the E measurement configuration, and the Gmap with an insert showing the PEF in a G measurement configuration,respectively. In the E and G maps shown in FIGS. 21A and 21B,respectively, the light colored region represented the E or G of thenormal breast tissues and the dark colored region indicated abnormallyhigh E and G signature of abnormal tissues. Clearly using the contrastin the E or G map, one could locate the abnormal tissue within theexcised sample and determine the size of the abnormal region. Both the Eand G are higher at the tumor site, an invasive ductal carcinomaexhibits a G/E>0.7, than at the surrounding tissue. With such detectionstrategy, PEFS has exhibited remarkably high detection sensitivity forabnormal breast tissues, namely about 100% sensitivity with p<0.01 forthe entire age group (age 24-90), for women under 40 and for women withnormal breast tissue elastic modulus and shear modulus similar to thoseof women under 40 (about 35% of the 71 cases were examined).

The PEFS was also found to be effective in accurately determining tumorsize. FIG. 22 shows a graph comparing the tumor size measurements usingthe PEFS and tumor size determined by pathology. The results werestatistically the same. It is important to note that 26 of these samplesincluded skin and nipple. Therefore, the results demonstrate that thepresence of skin and nipple did not affect the quality of the PEFSmeasurements. Table VII shows the average measured values of E and G forcarcinoma in situ (CIS), IC and benign tumors. As can be seen, thesevalues are 3-5 times that of the normal breast tissues, regardless ofpatient's age.

TABLE VII CIS IC Benign Elastic Modulus(E) 62 ± 10 kPa  55 ± 9 kPa 44 ±12 kPa Shear Modulus(G) 23 ± 10 kPa 40 ± 10 kPa 24 ± 10 kPa p value<0.01 <0.01 <0.01

Table VIIII shows that different type of tumors exhibited different G/Eratios. For example, the dark colored region in FIG. 21C indicatedG/E>0.7 which corresponded to IC.

TABLE VIIII G/E = 0.3 G/E = 0.5 G/E > 0.7 Sub Total Malignant 10 2 35 47Invasive Carcinoma 2 2 34 38 Carcinoma in situ 8 1 9 Benign 6 13 5 24Total 16 15 40 71

Thus, as shown in Table IX, with G/E>0.7 alone and G/E>0.7 or G/E=0.3,it was possible to predict invasive carcinoma and malignant tumors(including both IC and CIS) with 89% sensitivity and 82% specificity,and 96% sensitivity and 54% specificity, respectively.

TABLE IX Sensitivity Specificity Malignancy 96% (45/47) 54% (13/19)Invasiveness 89% (29/33) 82% (24/28)

Of the 71 ex vivo breast tissue samples, 25 cases had a high elasticmodulus and shear modulus, as shown in FIG. 20, representative ofmechanically dense breast tissue. As discussed above, the detectionsensitivity of abnormalities in these 25 cases with mechanically densebreast tissue was also 100%. Moreover, using the same G/E criteriadiscussed above, a diagnosis of invasive carcinoma in these 25 sampleswas determined with 93% sensitivity and 80% specificity and a diagnosisof malignancy in these 25 samples was determined with 94% sensitivityand 63% specificity (see Table X), which was essentially the samesensitivity and specificity as for the entire age group. This datafurther supports the conclusion that PEFS were able to detect breasttumors in dense breast tissue as well as in other breast tissue.

TABLE X Sensitivity Specificity Malignancy 94% (16/17) 63% (5/8) Invasiveness 93% (14/15) 80% (8/10)

Example 7

The use of the PEFS in excised breast tumors has been evaluated in thelaboratory. A lumpectomy specimen was taken from a 60-year old womanwith breast cancer. The known malignancy was 1.4 cm in the largestdimension. After surgical excision, the specimen was oriented with silksutures, scanned with ultrasound, and images were stored. The PEFS scanwas performed in the same orientation to allow later correlation withthe ultrasound image. The specimen was sectioned in the same orientationto allow histological confirmation of the PEFS findings as well. Usingthe PEFS, preliminary elastic modulus measurements were performed onbreast lumpectomy samples using an 8 mm wide PEFS with a rectangulartip. A lateral elastic modulus profile of a lumpectomy sample, measuredwith an 8 mm wide PEFS, was able to distinguish cancerous tissue fromthe surrounding tissues. The PEFS scan was able to identify a large15×13×12 mm invasive ductal carcinoma and a smaller 6×5×3 mm satelliteinvasive ductal carcinoma. Notably, this smaller lesion was not detectedby mammogram, ultrasound or the physician's preoperative palpation. Thelocation and size of the detected tumors were verified by pathologymeasurements.

Example 8

A 51 year old patient with a possible breast tumor on the right side (10o'clock) of her right breast was examined. Mammography missed the tumor.FIG. 23A shows a robotic arm positioning a PEFS array on the patient'sbreast while the patient was in a supine position. The PEFS array isconstructed from 4 individual PEFS sensors as shown in FIGS. 26A-26D. Aclose-up of the PEFS array is shown in FIG. 23B. The patient's skin wasmarked with 7 reference labels at 10 mm intervals indicating theposition of the tumor. The PEF array was moved over the reference labelsfrom left to right. The measurements were carried out with one PEFS at atime. The depth sensitivity limit was about 2 cm. FIG. 24 shows themeasurements obtained by the PEFS. The elastic modulus of the tumorregion was about 28 kPa whereas the elastic modulus of the rest of thearea was about 10-11 kPa. Based on this information, it was deduced thatthe tumor was about 2.5 cm×1.7 cm, which was close to the actual 2.5 cmsize of the tumor that was determined by pathology.

The same tumor was also evaluated using two PEFS' in sync. The elasticmodulus measurement over the tumor with two PEFS' in sync was about 38kPa. The elastic modulus of normal breast tissue also increased,indicating that when two PEFS' were operated in sync, the measurementsalso include part of the chest wall due to the doubling of depthsensitivity. This suggests that the depth sensitivity of the PEFS arraywas adequate.

Both the PEFS and PEFS array successfully located the tumor and the PEFSarray accurately determined its size. Additionally, the patient noted nodiscomfort during the procedure.

Example 9

FIG. 25 shows the depth detection sensitivity of a plurality of PEFS andPEFS arrays having different dimensions. The results show that thesePEFS and PEFS arrays demonstrated a depth sensitivity of about twice thewidth of the respective PEFS and PEFS array. As can be seen in FIG. 25,an array of four 8 mm wide PEFS' that were operated in sync, having acombined width of about 32 mm, showed a depth sensitivity as high asabout 63 mm, which is twice the width of the tissue contact area.

Example 10

To decrease the scan time for patient screening and improve the deviceperformance, a PEFS system including an n×1 PEFS array having a contactarea of about 4-10 cm, a portable measurement unit and a robotic arm forautomatic rapid scanning can be constructed. Each PEFS will be about a 3cm long and about 8-10 mm wide and will have a top PZT layer 3 cm long,8-10 mm wide and 127-μm thick (T105-H4E-602, Piezo Systems Inc.,Cambridge, Mass.) for force application and a 2-cm long bottom PZT layerof the same thickness and width for sensing. The top and bottom PZTlayers may be bonded to a 50-μm thick stainless steel layer (Alfa Aesar,Ward Hill, Mass.) of the same width in the middle using a nonconductiveepoxy (Henkel Loctite Corporation, Industry, Calif.) cured at roomtemperature for one day. The tip of the stainless steel middle layerwill be fashioned into a square loop at the free end with each side ofthe square equal to the width of the cantilever to facilitate bothcompression and shear measurements. The PEFS' will be clamped inside aholder, shown in FIGS. 26A and 26B, with a top that can be screwed on,as shown in FIG. 26C, and a bottom that can also be screwed on, as shownin FIG. 26D, to help protect the PEFS' and flatten the breast surface toensure a full contact between the PEFS' surfaces and the breast formeasurement accuracy.

For elastic modulus measurements, the PEFS' of the array will beoriented parallel to the tissue surface and will be positionedhorizontally, similar to FIG. 23A. To measure the shear modulus, thePEFS' of the array will be oriented perpendicular to the tissue surface.The arrangement of the PEFS array will be such that the contour of thecontact area of the array best matches that of the contour of thebreasts. The size of the array may vary to best adapt to breasts ofdifferent sizes.

The PEFS' array will be used to scan excised tissues to obtain E and Gmaps. From the E or G maps, it will be possible to determine the tumorsize using the width at half peak E or G value. For determination oftumor depth, two PEFS' of different contact areas in an array will beused to take measurements at the same location. The type of tumor, andthe malignancy and invasiveness of the tumor will be correlated with theobtained G/E ratio, and the size, location, and tumor type will becompared with the results of ultrasound and pathology for validation

To establish that the PEFS' array can detect breast cancers in youngwomen and women with mammographically dense breasts, PEFS' measurednormal-tissue elastic and shear modulus in the ex vivo samples will becompared with breast density determined by mammography.

The PEFS will also be used to probe patients. Accuracy for detection ofcancerous versus non-cancerous tissue, tumor margins, and tumor centersas well as normal-breast tissue elastic modulus and shear modulus willbe determined. The abnormality detection efficacy in women withpathology of all types, breast sizes and densities will be evaluated.PEFS scan will be correlated with the histological sections to confirmthe borders of the tumor and characteristics of the normal and malignanttissue. The experiment will also compare in vivo as well as ex vivonormal-tissue E and G obtained using the PEFS with the patient'smammographic density. The in vivo and ex vivo results tumor size andlocation, and tumor type will also be compared.

Example 11

Three PEFS' were used to determine the precise location and position ofan inclusion, representative of abnormal tissue, in a gelatin tissuesample model. The cantilevers were built with Lead Zirconate Titanate(PZT) sheets, 127 microns thick, (T105-H4E-602, Piezo Systems, Inc.,Cambridge, Mass.) and stainless steel 304 foil, 50 microns thick (AlfaAesar, Ward Hill, Mass.).

The two layers of sample model had a total thickness of 2 mm. Becausethe probes are to measure into but not further than the bottom “fat”layer of the model, the probes have diameters inside the range of 0.5 mmto 1 mm To determine T_(skin), E_(skin), and E_(fat), three cantileverswith three different probe contact areas are used. The cantilevers havevarying probe contact areas in order to achieve depth sensitivities inthe range of human skin. Table XI below shows the probe sizes and theresulting sensing depth for each of the three cantilevers. Probes forthe cantilevers were made from galvanized steel wire (24, 22, and 20gauge). The wires were cut with wire cutters to lengths of about 2 mmand glued to the free end of the cantilevers with superglue as follows:

TABLE XI Probe Contact Diameter Sensing Depth (mm) (mm) Cantilever A0.559 1.118 Cantilever B 0.711 1.422 Cantilever C 0.914 1.828

A k value under 175 N/m gives the cantilevers the proper flexibility tocomply with skin and keeps the strain that the sample/patient mustendure to a minimum (<10%).

FIG. 28 is a diagram of the skin model used to demonstrate measurementof T_(skin), E_(skin), and E_(fat). The model is made with materialsthat exhibit properties of human skin (Versaflex CL300 from GLS Corp,E=500 kPa) and subcutaneous fat (Lab Gelatin Type B, E˜10 kPa). Thesematerials meet our criteria for the model to have the proper E for skinon the top layer and E for fat on the bottom layer.

Measuring E_(skin), E_(fat), and T_(skin).

E is measured using an indentation test. Applying voltage to the drivinglayer of PZT moves the probe into the sample a distance, d. Becauseinduced voltages (V_(in)) in the sensing PZT layer are linear todisplacement of the free end of the cantilever we the induced voltagescan be correlated to displacement, d. Induced voltages and displacementsresulting from a range of applied voltages with and without a sampleunder the probe will be measured with an oscilloscope and a laserdisplacement meter respectively. The resistive force that the sampleexerts back on the probe inhibits the displacement resulting from theapplied voltage. V_(in,o) (the induced voltage with no sample) andV_(in) (the induced voltage with a sample) for several applied voltages(V_(a)) are used to calculate effective modulus (E_(eff)) of the entiresample (not individual layers). E is related to V_(in) by the followingequation:

${Eeff} = {{\frac{x}{v_{in}}\mspace{14mu} {where}\mspace{14mu} X} = {\frac{1}{2}\left( \frac{\pi}{A} \right)^{\frac{1}{2}}\left( {1 - v^{2}} \right){K\left( {V_{{in},o} - V_{in}} \right)}}}$

where v is the Poisson's ratio of the top layer material.K is the effective spring constant of the contlever, and A is thecircular contact area of the probe

The slope of X versus V_(in) for the six applied voltages gives theeffective E of the sample. Because there are three cantilevers withthree different probing depths, three different effective E values ofthe sample (E_(A), E_(B), and E_(c)) will be measured. These values willbe used to calculate T_(skin), E_(skin), and E_(fat) using a system ofequations that model the two layer model as two springs in a series.

The spring constants of two springs in a series add as follows:

$\begin{matrix}{\frac{1}{k\mspace{14mu} {effective}} = {\frac{1}{k\; 1} + \frac{1}{k\; 2}}} & {\mspace{385mu} (4)} & \;\end{matrix}$

The two layers of the model are also in series, so their springconstants add in the same manner. For this model, k1 is the springconstant of the top “skin” layer and k₂ is the spring constant of thebottom “fat” layer. Since

$\begin{matrix}{k = \frac{E\mspace{14mu} {of}\mspace{14mu} {Layer}}{{Depth}\mspace{14mu} {of}\mspace{14mu} {Layer}}} & {\mspace{410mu} (5)} & \;\end{matrix}$

then

$\begin{matrix}{{k\; {eff}} = \frac{E\; {eff}\mspace{14mu} \left( {E_{A},{E_{B}\mspace{14mu} {or}\mspace{14mu} E_{C}}} \right)}{{Depth}\mspace{14mu} {Sensitivity}\mspace{14mu} \left( {D_{A},D_{B},{{or}\mspace{14mu} D_{C}}} \right)}} & {\mspace{169mu} (6)} & \;\end{matrix}$

FIG. 27 illustrates how E_(A), E_(B), and E_(c) are composed of E_(skin)and E_(fat) and relate to equations 4, 5 and 6 above. The followingsystem of equations can be derived using equations 4, 5, and 6:

$\quad\begin{matrix}\begin{matrix}{{{For}\mspace{14mu} {Cantilever}\mspace{14mu} A\text{:}\mspace{14mu} \frac{1}{E_{A}/D_{A}}} = {\frac{1}{{Eskin}/{Tskin}} + \frac{1}{{Efat}/\left( {D_{A} - {Tskin}} \right)}}} & {\mspace{14mu} (7)} \\{{{For}\mspace{14mu} {Cantilever}\mspace{14mu} B\text{:}\mspace{14mu} \frac{1}{E_{B}/D_{B}}} = {\frac{1}{{Eskin}/{Tskin}} + \frac{1}{{Efat}/\left( {D_{B} - {Tskin}} \right)}}} & (8) \\{{{For}\mspace{14mu} {Cantilever}\mspace{14mu} C\text{:}\mspace{14mu} \frac{1}{E_{C}/D_{C}}} = {\frac{1}{{Eskin}/{Tskin}} + \frac{1}{{Efat}/\left( {D_{C} - {Tskin}} \right)}}} & (9)\end{matrix} & \;\end{matrix}$

E_(A), E_(B), and E_(c) are measured values, D_(A), D_(B), and D_(c) areknown (twice the diameter of the probe), and therefore the only unknownsin equations 7, 8 and 9 are T_(skin), E_(skin), and E_(fat). By solvingthe system of equations, values for these three unknowns can becalculated.

The foregoing examples have been presented for the purpose ofillustration and description and are not to be construed as limiting thescope of the invention in any way. The scope of the invention is to bedetermined from the claims appended hereto.

The below list of references is incorporated herein in their entirety.

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1. A method for evaluating tissue to predict the presence of one or moreconditions selected from the group consisting of tumor malignancy, tumorinvasiveness, and a presence and type of cancerous tissue, comprisingsteps of: applying a set of shear forces to a plurality locations onsaid tissue using at least one sensor comprising a piezoelectricmaterial; detecting at least a set of shear displacements resulting fromapplication of said set of shear forces on said tissue using saidsensor; determining net shear forces exerted on said locations from thecombination of applied shear forces and countering shear forcesresulting from tissue deformation; and deducing shear moduli of saidtissue at said locations from the net shear forces and a correspondingshear displacement; applying a set of compressive forces to saidlocations on said tissue using said at least one sensor comprising apiezoelectric material; detecting at least a set of compressivedisplacements resulting from application of said compressive forces onsaid tissue using said sensor; determining net compressive forcesexerted on said locations from the combination of applied compressiveforces and countering compressive forces resulting from tissuedeformation; deducing a corresponding compressive displacement; deducingelastic moduli of said tissue at said locations from the net compressiveforces; creating a map of a ratio of said shear modulus to said elasticmodulus for said tissue at said locations; and evaluating said tissue topredict the presence of one or more conditions selected from the groupconsisting of tumor malignancy, tumor invasiveness and a presence andtype of cancerous tissue, based on at least one of said elastic moduliand shear moduli, in combination with said map of ratios of said shearmodulus to said elastic modulus for said tissue. 2-3. (canceled)
 4. Themethod of claim 3, wherein said shear force is exerted substantiallyperpendicular to a surface corrugation of said tissue.
 5. The method ofclaim 4, wherein said evaluating step predicts the presence of invasivecarcinoma when said ratio of shear modulus to elastic modulus is greaterthan 0.7.
 6. The method of claim 4, wherein said evaluating steppredicts the presence of tissue malignancy when said ratio of shearmodulus to elastic modulus is greater than 0.7 or when said ratio shearmodulus to elastic modulus is between 0.3 and 0.4 and one of said shearand elastic moduli of said tissue is greater than a shear or elasticmoduli of healthy tissue.
 7. (canceled)
 8. The method of claim 4,wherein said evaluating step predicts the presence and type of abnormaltissue.
 9. The method of claim 8, wherein said evaluating step predictsthe presence of hyperplasia when said ratio of shear modulus to elasticmodulus is from 0.4-0.6.
 10. The method of claim 9, wherein saidevaluating step predicts the presence of hyperplasia when said ratio ofshear modulus to elastic modulus is about 0.5.
 11. The method of claim8, wherein said evaluating step predicts the presence and type ofabnormal tissue based on one of the shear modulus and elastic modulusbeing different from the shear modulus or elastic modulus of healthytissue, a location of the tissue and the ratio of the shear modulus tothe compressive modulus being from about 0.3 to about 0.4.
 12. Themethod of claim 11, wherein said cancerous tissue is a carcinoma insitu.
 13. The method of claim 1, wherein said at least one sensor is anarray comprising a plurality of sensors arranged to be capable ofsimultaneously applying a shear or compressive force to at least onelocation on said tissue.
 14. The method of claim 1, wherein saidcompressive force is an indentation compressive force.
 15. The method ofclaim 1, wherein said at least one sensor comprises a driving electrodeand said steps of applying shear and compressive forces to said locationon said tissue comprise the step of applying a set of voltages to saiddriving electrode.
 16. The method of claim 1, wherein said method isused to screen for, identify or diagnose a type of cancer selected fromthe group consisting of breast cancer, prostate cancer, skin cancer, orliver cancer.
 17. The method of claim 1, wherein said method furthercomprises the step of performing at least one additional procedureselected from the group consisting of: a biopsy, a surgery, amammography, radioactive imaging and electromagnetic imaging.
 18. Themethod of claim 1, further comprising the step of enhancing an indicatorof malignancy, invasiveness or tumor type.
 19. The method of claim 18,wherein said step of enhancing said indicator comprises the step ofincreasing a perceived interfacial roughness of a tumor.
 20. The methodof claim 19, wherein said step of increasing the perceived interfacialroughness of a tumor comprises the step of applying a shear force alonga scan path at an angle greater than 60 degrees to surface corrugationsof said tissue.
 21. The method of claim 20, wherein said angle is about90 degrees.
 22. The method of claim 1, wherein the tissue isheterogeneously dense breast tissue.
 23. The method of claim 1, whereinthe tissue is extremely dense breast tissue. 24-26. (canceled)